A goal of modern cancer therapy is to identify molecules in signal transduction pathways that affect cell growth, and particularly those that cause a normal cell to become cancerous. One such pathway is the RAF-MEK-ERK pathway, and the up-regulation of one or more of its members is thought to be responsible for a number of cancers. For example, patients with chronic myelogenous leukemia, herein after referred to as CML, who are in either the chronic or blast phase typical achieve remissions in response to the marketed drug Gleevec™, also referred to as imatinib or STI571 (N. Eng. J. Med. 244, 1031 [2001]; N. Eng. J. Med 244, 1038 [2001]). CML is characterized by the Philadelphia chromosomal translocation (Ph+) resulting in a Bcr-Abl fusion protein. Imatinib treats CML by blocking Bcr-Abl kinase activity.
While the remissions achieved with imatinib during the chronic phase of CML are durable, patients with remissions achieved during the blast phase usually relapse within 2-6 months (N. Eng. J. Med. 244, 1038 [2001]). Resistance to Imatinib results in reactivation of Bcr-Abl kinase activity. Recently, it has been shown that these relapses are usually due to imatinib-resistance that occur either by over-expression of the translocated Bcr/Abl gene, or mutation of the imatinib target gene, namely the Abl kinase (Science 293, 876 [2001]). Resistance often correlates with mutations in the Abl kinase domain, including T315I and E255K.
The Abl kinase was chosen as a molecular target in the treatment against cancer since 95% of patients with CML have activation of the Abl pathway that occurs through chromosomal translocations that result in fusion of the Bcr and Abl genes. As mentioned above, a key pathway that is up-regulated in CML cells that are resistant to imatinib is the RAF-MEK-ERK pathway. Therefore, treatment with inhibitors of the RAF-MEK-ERK pathway should lead to remissions in patients with imatinib resistant CML.